Pharmaceutical products for curing and preventing illnesses connected with the malfunction of vascular endothelial cells

ABSTRACT

The invention relates to a method of treating or preventing illnesses resulting from damaged endothelial cells, wherein the method comprises administering to a patient a product comprising hydroxylamine derivatives of the general formulae (I) ##STR1## with the proviso that in the compounds of general formula (I) when X comprises a --NR 3  R 4  group and Y comprises a hydroxyl group, the X group is condensed with the Y substituent to form an intramolecular ring represented by general formula (Ill) ##STR2##

This is a 371 of PCT/HU97/00044 filed Aug. 6, 1997.

TECHNICAL FIELD OF THE INVENTION

The invention concerns products for curing or preventing diseasesresulting from the damaging of the vascular endothelial cells, whichcontain a hydroxylamine-derivative of general formula (I) or (II) as theeffective agent.

BACKGROUND OF THE INVENTION

The normal functioning of the vascular endothelial cells is of crucialimportance for the body. These cells form an edge surface between thecirculating blood and the elements of the vein wall performingthrombogenous activity. The role of the vascular endothelial cells inhomeostasis is quite varied:

they participate in the two-way transport of substances originating fromthe blood and the tissues,

they form a barrier for the macromolecules,

these cells are the location of the synthesis and the decomposition ofthe mediators acting in the regulation of the interaction between thecellular elements of the vein wall and the blood (e.g. fibrinogen,collagen, proteoglycanes, PGI₂, EDRF (NO), EDHF, endothelin-1,angiotensin-II),

they initiate the migrational, proliferative, and thrombolytic processescontributing to histic reparation,

they sustain the thromboresistance of the vein wall [Rubanyi, G., J.Cardiovasc. Pharmacol. 1993, 22 (42. Suppl., p S1-14]

The impairment of the endothelium results in atherosclerosis. Theimpairment leading to the deterioration of the endothelium can occur atmechanic intervention, for example catheterisation, and also as theresult of biochemical and immunological processes.

As the first step of the formation of atherosclerotic plaque, cellsfilled with lipids accumulate in the intima of the arteries (SteinbergD. et al., JAMA 264-304, 1990). These cells--especially monocytes andmacrophages originating from the blood--first stick to the endothelium,and then penetrate the intima. The injury of the endothelial cells mayalso contribute to the adhesion, although no morphological alteration isvisible in the early phase. The oxidation of the LDL particles mayresult in their incorporation by the monocytes located in the intima,and the monocytes thus become foam cells. These foam cells form thelipid-streaks, the earliest form of arteriosclerotic alteration.

In the later stages, bleeding, necrosis, neovascularisation, andsclerosis occur, and in the course of these, the intergrown plaqueforms, which then taper the arteries (Ip. JH, Fuster et al., J. Am.Coll. Cardiol 15:1667, 1990).

Thrombosis may occur at various stages of atherosclerosis. Repeatedthrombosis leads to vascular obstruction and thromboembolic illnesses,such as coronary thrombosis, the thrombosis of the brain vessels, orperipheral vascular illnesses.

In a clinical sense, "endothelial dysfunction syndrome" refers togeneralised or localised vessel spasm, thrombosis, arteriosclerosis, andrestenosis. Attempts to cure these illnesses have includedinterventional clinical techniques, bypass surgery, and medicinaltreatment.

Only a few existing drugs may be suitable for the "treatment" ofendothelial dysfunction. They fall into four major categories:

substitution for natural "protective" endothelial substances (e.g.stable analogues of PGI₂, nitro-vasodilators, rt-PA /recombinant tissueplasminogen activator/)

inhibitors or antagonists of endothelium-derived contracting factors(e.g. ACE inhibitors, angiotensin II receptor antagonists; TXA₂-receptor antagonists)

cytoprotective agents (e.g. the free-radical scavengers superoxidedismutase and probucol, and free radical production inhibitor lazaroids)

lipid-lowering drugs.

Although none of them were originally designed for this target, theiralready proven clinically beneficial effects in the case of certainillnesses may involve the protection or restoration of normalendothelial function. The rationale behind innovative therapies in thiscategory is the restoration of normal endothelial cell lining, wherethese cells themselves will "do the job". Potential approaches mayinclude stimulation of regrowth of normal endothelium, or by newemerging therapeutic modalities based on recombinant DNA technology(Science 1990; 249: 1285-8). According to the data available, norecognised drug fulfils these criteria.

These days no medicine or medicine-candidate is known to act directly onthe endothelium, and thus none is suitable for treating endothelialdysfunction. Therefore, there is great therapeutical demand for amedicine which is capable of preventing, reversing, or at least slowingdowin the formation of complication symptoms, or decreasing theoccurrence of the illness.

SUMMARY OF THE INVENTION

In the course of our research we have found that thehydroxylamine-derivatives of general formula (I) and (II) perform astrong protecting and regenerative effect on vascular endothelial cells,and are capable of preventing. their impairment of various origins.

In the general formulae (I) and (II), R¹ and R² independently refer to ahydrogen atom or a straight or branched alkyl group of 1 to 6 carbonatoms, or R¹ and R² together with the nitrogen atom in-between form asaturated 5-7 membered heterocyclic group, containing optionally furthernitrogen and/or oxygen heteroatoms,

A refers to a straight or branched alkyl group of 4 to 12 carbon atoms,a phenyl group, substituted or unsubstituted, containing preferably analkyl-, haloalkyl- or nitro group as substituent, or a 5-6 memberedheteroaromatic ring containing nitrogen, oxygen or sulphur,

in the compounds of general formula (I), Z refers to a covalent bond,and in the compounds of general formula (II) to a covalent bond or a ═NHgroup,

in the compounds of general formula (I), X refers to a halogen atom orto a --NR³ R⁴ group, wherein R³ and R⁴ independently refer to a hydrogenatom or a straight or branched alkyl group of 1 to 6 carbon atoms, whilein the compounds of general formula (II) X refers to an oxygen atom,

in the compounds of general formula (II), R' refers to a hydrogen atomor a straight or branched alkyl group of 1 to 6 carbon atoms, and

in general formulae (I) and (II), Y refers to a hydrogen atom, ahydroxyl group or an acyloxy group, which contains preferably the acylpart of a long chain fatty acid of 8 to 22 carbon atoms, or of a cyclicaromatic carboxylic acid as its acyl component,

and in the compounds of general formula (I) wherein X refers to a --NR³R⁴ group and Y refers to a hydroxyl group, the X group is condensed withthe Y substituent and forms an intramolecular ring.

The salts and the optically active forms of these compounds are alsoeffective compounds.

Those compounds of general formula (I) that have X referring to a --NH₂group, and A referring to an unsubstituted phenyl- or pyridyl-group, andin which Y refers to a hydroxyl group are already known from thepublished French patent application of No. 2362 845 A1. These compoundsare, according to the above quoted patent application, selectivebeta-blockers, and are thus suitable for the treatment of diabeticangiopathy.

Those compounds of general formula (I) that have X referring, to ahalogen atom, Y referring to a hydroxyl group, and A to an unsubstitutedor substituted phenyl- or pyridyl-group are already known from thepublished PCT patent application of No. WO 90/04584 A1. These compoundshave a selective beta-blocking effect, and are thus suitable aseffective agents in the treatment of diabetic angiopathy.

Those compounds of general formula (II) that have A referring to aphenyl- (unsubstituted or substituted by a haloalkyl-group), pyridyl-,or thienyl-group, Z referring to a covalent bond, R' referring to ahydrogen atom, and Y to a hydroxyl group are already known from theHungarian patent application of No. 2385/92, published under No.T/66350. These compounds have an anti-ischaemic and anti-angineticeffect, and are thus well usable in the therapy of vein complicationsconnected with diabetes mellitus.

Those compounds of general formula (I) that have A referring to anaromatic or heteroaromatic ring and X to a halogen atom, while Y refersto a hydrogen atom are already known from the published PCT patentapplication of No. WO 95/30649 A1. These compounds are of ananti-ischaemic effect, and can be best used in the treatment of theoccurrences of ischaemia of which hypertonic veins and thrombocyteaggregation are characteristic.

In none of the above quoted specifications is it written that thedescribed compounds should have any effect on the vascular endothelialcells.

As we have mentioned above, our research has proved the compounds ofgeneral formulae (I) and (II) to be effective on the endothelial cellsof the cardiovascular and the cerebrovascular systems. In theexperiments to be dealt with in detail later, it has been observed thatthese compounds are capable of blocking or restoring the damaging ofthese cells. Thus, these compounds may be used as effective substance intherapeutical products which are used in the treatment of illnessesresulting from the abnormal functioning or the damaging of theendothelial cells, especially cardiovascular and cerebrovascularillnesses, hypertension, hyperhomocysteinaemia, and peripheral vasculardiseases.

Based on this observation, the invention consists of the application ofthe hydroxylanmine derivatives of general formulae (I) and (II)--whereinR¹ and R² independently refer to a hydrogen atom or a straight orbranched alkyl group of 1 to 6 carbon atoms, or R¹ and R² together withthe nitrogen atom in-between form a saturated 5-7 membered heterocyclicgroup, containing optionally further nitrogen and/or oxygen heteroatoms,A refers to a straight or branched alkyl group of 4 to 12 carbon atoms,a phenyl group, substituted or unsubstituted, containing preferably analkyl-, haloalkyl- or nitro group as substituent, or a 5-6 memberedheteroaromatic ring containing nitrogen, oxygen or sulphur,

in general formula (I), Z refers to a covalent bond, and in generalformula (II) to a covalent bond or a ═NH group,

in general formula (I), X refers to a halogen atom or to a --NR³ R⁴group, wherein R³ and R⁴ independently refer to a hydrogen atom or astraight or branched alkyl group of 1 to 6 carbon atoms, while ingeneral formula (II) X refers to an oxygen atom,

in general formula (II), R' refers to a hydrogen atom or a straight orbranched alkyl group of 1 to 6 carbon atoms, and

in general formulae (I) and (II), Y refers to a hydrogen atom, ahydroxyl group or an acyloxy group, which contains preferably the acylpart of a long chain fatty acid of 8 to 22 carbon atoms, or of a cyclicaromatic carboxylic acid as its acyl component, however, in certaintypes of compounds of general formula (I) wherein X refers to a --NR³ R⁴group and Y refers to a hydroxyl group, the X group is condensed withthe Y substituent and forms the intramolecular ring represented bygeneral formula (III), in which formula A, Z, R¹ and R² have the samereference as above,

furthermore, of the salts and optically active forms of these compoundsfor the production of medicine used for the treatment or prevention ofillnesses connected with the dysfunction of the endothelial cells.

The invention also relates to pharmaceutical products used for thetreatment and prevention of illnesses in connection with abnormalfunctioning of the vascular cells which contain, as effective substance(apart from the usual carrier substances and auxiliary substances usedin pharmaceutical compositions) a compound of general formula (I) or(II) in 0.5-95.5 m/m %, or in certain cases the salts or opticallyactive forms of these compounds, and in these formulae the references ofR¹, R², A, Z, X, Y and R' are the same as above.

Those compounds of general formula (I) and (II) are preferred for theapplication described in the invention, wherein A refers to a pyridyl-,a thienyl-, or a phenyl-, nitrophenyl- or trifluoromethylphenyl group.Those compounds of general formula (I) are also preferred wherein Xrefers to a chloro atom or to a NH₂ group. Of these latter compoundsparticularly preferred are those which contain an intramolecular ringformed by the condensation of groups X and Y. Also preferred are thosecompounds of general formula (II), wherein R' refers to a hydrogen atom,and those compounds of general formula (I) or (II) wherein Y refers to ahydrogen atom or a hydroxyl group. In all these listed categoriespreferred are those compounds wherein the NR¹ R² group refers to apiperidino- or dialkylamino group.

The following compounds of general formula (I) and (II) are especiallypreferred for the invention:

N-[2-benzoyloxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidamide(Z)-2-butenedioate (1:1) (compound No. 1.)

N-[2-palmitoyloxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidamidemonohydrochloride (compound No. 2.)

N-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3-trifluoromethylbenzenecarboximidoylchloride monohydrochloride (compound No. 3.)

N-[2-hydroxy-3-(1-piperidinyl)propoxy]-2-thiophenecarboximidoyl chloridemonohydrochloride (compound No. 4.)

N-[2-hydroxy-3-(1-piperidinyl)propoxy]-benzenecarboximidoyl chloridemonohydrochloride (compound No. 5.)

N-[2-hydroxy-3-(1-piperidinyl)propoxy]4-pyridinecarboximidoyl chloride(Z)-2-butenedioate (1:1) (compound No. 6.)

N-[2-hydroxy-3-(1-piperidinyl)propoxy]-2-nitrobenzenecarboximidoylchloride monohydrochloride (compound No. 7.)

N-[3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloridedihydrochloride (compound No. 8.)

N-[3 -(1-piperidinyl)propoxy]-3-nitrobenzenecarboximidoyl chlorideMonohydrochloride (compound No. 9.)

N-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3-trifluoromethylbenzamide(compound No. 10.)

N-hexyl-N'-[2-hydroxy-3-(1 -piperidinyl)propoxy]-urea (compound No. 11.)

N-hexyl-N'-[3-(1-piperidinyl)propoxy]-urea (compound No. 12.)

5,6-dihydro-5-(1-piperidinyl)meithyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine(compound No. 13.)

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents a hydroxylamine derivative of general formula (I).

FIG. 2 represents a hydroxylamine derivative of general formula (II).

FIG. 3 represents a compound of general formula (III) which is acompound of general formula (I) wherein a nitrogen containing X group iscondensed with the Y substituent to form an intramolecular ring.

FIG. 4 represents an intermediate compound of general formula (IV),wherein X is --NH₂.

FIG. 5 represents an amidoxim of general formula (V).

FIG. 6 represents an epichlorohydrin of general formula (VI).

FIG. 7 represents an intermediate compound of general formula (VII).

FIG. 8 represents an epoxy compound of general formula (VIII).

FIG. 9 represents an amine of general formula (IX).

FIG. 10 represents a compound of general formula (X).

FIG. 11 represents an acid chloride of general formula (XI).

FIG. 12 represents a halogen-based compound of general formula (XII).

FIG. 13 represents an alkali-hydroxamate of general formula (XIII).

FIG. 14 represents an amino compound of general formula (XIV).

FIG. 15 represents an isocyanate-based compound of general formula (XV).

FIG. 16 represents a compound of general formula (XVI).

Those compound of general formula (I) in which X refers to halogen atommay be prepared by reacting an amidoxim of general formula (V), whereinA has the same reference as above with an amino-chloro-propanederivative, wherein R¹, R² and Y have the same references as above andthe --NH₂ group of the resulting intermediate of general formula (IV),wherein Z refers to covalent bond while the other substituents have thesame references as above is replaced with a halogen atom by diazotation.In cases when a compound of general formula (I) containing a hydroxylgroup as Y substituent is produced the necessary amino-chloro-propanederivative of general formula (XII) containing a hydroxyl group as Ysubstituent may be produced from epichlorohydrin of formula (VI) and anamine of general formula (IX), wherein R¹ and R² have the samereferences as above. An alternative procedure is to react theepichlorohydrine with the amidoxim of general formula (V) first, andthen to diazotate the resulting intermediate of general formula (VII),wherein A refers to the same as above and to react the epoxy-compound ofgeneral formula (VIII), wherein A refers to the same as above with theamine of general formula (IX).

Those compounds of general formula (I), wherein Y refers to an acyloxygroup may be produced by a reaction of the suitable compounds of generalformula (I) containing a hydroxyl group in the place of Y, and acidchlorides of general formula (XI), wherein R⁵ refers to a long chainalkyl or to an aryl group.

The compounds of general formula (II) containing covalent bonds in theplace of Z may be produced by one of the following methods:

(i) connecting an alkali-hydroxamate of general formula (XIII) wherein Aand R' have the same reference as above and K refers to the cation of analkaline metal, and a halogen compound of general formula (XII) whereinR¹, R² and Y have the same references as above, or

(ii) the reaction of an amino compound of general formula (XIV) whereinR¹, R², Y and R' have the same reference as above, and an acidhalogenide wherein A has the same reference as above,

while those compounds of general formula (II) which contain a covalentbond in the place of Z, and a hydrogen atom in the place of R' may alsobe produced--beyond methods (i) and (ii)--by the following methods:

(iii) the diazotation in a halogen-free environment of a suitablecompound of general formula (I) containing a --NH₂ group in the place ofX, and a covalent bond in the place of Z, or

(iv) the hydrolysis of a suitable compound of general formula (I)containing a halogen atom in the place of X.

Those compounds of general formula (II) wherein A refers to an alkylgroup and Z refers to a ═NH group may be produced by the reaction of acompound of general formula (II) wherein R¹, R², Y and R' have the samereferences as above, in an organic solvent, preferably in chloroform,with an equimolar amount if alkylisocyanate wherein A refers to an alkylgroup.

The compounds of general formula (III) are special cases of thecompounds of general formula (I) wherein a nitrogen containing X groupis condensed with the Y substituent to form an intramolecular ring.

Such compounds may be produced by the reaction of a compound of generalformula (I) (wherein Y refers to a hydroxyl group) with an excess ofthionyl chloride, followed by the ring closure of the resultingintermediate compound of general formula (IV) (wherein Y refers to achlorine atom, while the other substituents have the same references asabove) with an excess of potassium-terc-butoxide boiled in an organicsolvent (preferably in t-butanol).

The hydroxylamine derivatives of the invention bear surprisingpharmacological properties. It is to be noted especially, that they donot only regenerate the endothelial cells morphologically, but alsofimctionally, that is, due to their effect the endothelial cells of thegood tolerability of these compounds is also remarkable. Thesecharacteristics form the grounds for the pharmaceutical use of thehydroxylamine derivatives of general formulae (I) and (II). Thesemedicines may be used to treat cardio- and cerebrovascular diseases ofhumans and animals, such as hypertension, hyperhomocysteinaemia andperipheral vascular diseases.

Among cardiovascular diseases, these compounds may be best used in thecases of coronary artery diseases, atheroschlerosis, restenosisfollowing balloon angioplasty, and coronary bypass surgery, and amongcerebrovascular diseases in the cases of cerebral artery occlusion, thehydroxylamine derivatives of general formulae (I) and (II) may also beapplied, in the treatment of hypertension against cases resulting fromessential, renal, pulmonal and endocrine diseases, while in the therapyof peripheral vascular diseases they are best used when aortic stenosisoccurs in the legs.

The compounds of the invention may also be used to counteractsusceptibility for illness due to the genetically determined ortemporary weakening of the protective mechanism. The usual dose dependson the patient treated and the illness in hand and may vary in the rangeof 0.1-200 mg/kg, preferably of 1-50 mg/kg, daily. This may mean, forexample, that a daily dose for human therapy is between 10 to 200 mgorally, 1 to 15 mg rectally, or 2 to 20 mg parenterally, for adultpatients.

Suitable pharmaceutical compositions may be for example solid substancesor liquids, in any kind of drug formulations generally used in human orveterinary therapy, such as simple or coated tablet, gel capsule,granulates, solution, syrup, suppository, lyophilised or not lyophilisedinjectable product; these may be produced by the usual methods. Theeffective substance may be carried by the vehicles usual for these typesof pharmaceutical products, such as talc, gum Arabic, lactose, starch,magnesium stearate, cocoa-butter, aqueous or non-aqueous carriers,animal or plant greases, paraffin derivatives, glycols, variousmoistening, dispersing, or emulgating substances and preservatives.

The biological effects of the compounds of the invention represented bythe general formulae (I) and (II) are illustrated through the followingresults of the vasorelaxing effect test performed in vitro on rats, andof the thoracic aorta morphological test. Three-month-old, spontaneouslyhypertensive (SH) rats were treated for 1 month with the various testedcompounds.

THE VASORELAXING EFFECT OF THE TESTED HYDROXYLAMINE DERIVATIVES ON THETHORACIC AORTA OF THE SH RATS (IN VITRO TEST)

The test was performed according to the method known from the applyingliterature [Japan J. Pharmacol., 59, 339-347 (1992)]. The SH rats werenarcotised with Nembutal (40 mg/kg, i.p.), and their thoracic aorta wasthen taken out and placed in an oxygenated (95% O₂ +5% CO₂)Krebs-Henseleit solution. The composition of the solution (mM): NaCl118, KCl 4, 7, CaCl₂ 2, 52, MgSO₄ 1, 64, NaHCO₃ 24, 88, KH₂ PO₄ 1, 18,glucose 5, 5. The 3 mm long aortic rings were suspended in a 20 ml organbath of 37° C. The resting tension was 1 g, which was sustainedthroughout the experiment. During the 1 hour equilibration period themedium of the organ bath was changed every 20 minutes. The vessels werecontracted with 10⁻⁶ M methoxamine (approx. 80% of max. contraction).After reaching the maximum contraction, the vasodilation induced byacetylcholine (Ach) (10⁻⁶ -10⁻⁴ M) and functional integrity of theendothelium was tested. The contraction force was measured with anisometric strain gauge probe (SG-01D, Experimetria Ltd), and registeredon an OH-850 polygraph (Radelkis). The results of the tests aresummarised in table No. 1.

                  TABLE 1                                                         ______________________________________                                        The vasorelaxing effect of the compounds of the invention                       on the thoracic aorta of SH rats (in vitro test)                                                Ach doses (M)                                             Substances/Doses    10.sup.-6                                                                              10.sup.-5                                                                            10.sup.-4                                 ______________________________________                                        SH control, n = 10  53.8     55.6   71.0                                        Compound no. 13., n = 12; 20 mg/kg 79.6 86.0 95.9                             Compound no. 5., n = 11; 5 mg/kg 82.3 84.5 87.2                               Compound no. 4., n = 11; 20 mg/kg 75.6 79.8 80.5                              Compound no. 6., n = 10; 5 mg/kg 87.5 87.9 84.4                               Compound no. 10., n = 12; 10 mg/kg 64.8 63.7 78.0                             Compound no. 1., n = 12; 20 mg/kg 74.7 58.7 82.7                              Compound no. 2., n = 10 80.4 75.6 88.0                                        Compound no. 11., n = 12; 20 mg/kg 88.1 91.3 91.9                             Compound no. 8., n = 10; 5 mg/kg 74.1 75.3 80.9                               Compound no. 3., n = 8; 10 mg/kg 76.4 77.2 84.8                               Compound no. 12., n = 12; 10 mg/kg 66.3 67.2 84.1                             Compound no. 7., n = 11; 5 mg/kg 81.7 86.0 95.9                               Captopril, n = 8; 20 mg/kg 88.7 88.2 94.2                                   ______________________________________                                    

As it is apparent from the table, in the cases of untreated hypertoniccontrol animals the relaxation, provoked by the administration of 10⁻⁴ Macetylcholine decreased to 71%, which is due to the endothelium damagecaused by hypertension. The tested compounds improved this decreasingvasodilation significantly, which shows the improvement of theendothelial function.

THE MORPHOLOGICAL EXAMINATION OF THE THORACIC AORTA WITHELECTRONMICROSCOPE

This test was performed according to the applying literature (Br. J. ofPharmacol., 1995; 115, 415-420). 1 mm² segments of the aorta-wall of thethoracic aorta of the rats were cut out, which were then fixed at roomtemperature with 2.5% glutaraldehyde. This was followed by apost-fixation with 1% osmium tetroxide, which lasted for one hour.Afterwards, the tissue segments were dehydrated with ethanol, and beddedinto Durcupan ACM. The excisions were evaluated in a qualitative mannerbased on the photograph taken on a Hitachi 7100 electronmicroscope. Theresults of these tests are shown in table No. 2.

The results of the morphological tests were expressed on a scale of 1 to5, depending on the extent to which the treatment with the testedcompounds restored the endothelial damage caused by hypertension, thatis, the extent of regenerating activity. On the scale, 1 representscases where there was no regeneration to be observed, 2 stands for weak,3 for medium, 4 for good, while 5 represents strong regeneration.

In comparison with the untreated control significant protective orregenerative effect was observed after treatment with the hydroxylaminederivatives of general formulae (I) and (II) of the invention. Due tothe treatment, a thin protective layer formed over the injuredsubendothelium, which was composed of cells containing an active nucleusand rich cytoplasm. Regeneration appeared quite effective in themajority of the cases.

                  TABLE 2                                                         ______________________________________                                        The electromicroscopic evaluation of the effects of the compounds              of the invention on the thoracic aorta of SH rats (morphological test)            Substances         Extent of                                                                      Doses Regeneration                                   ______________________________________                                        SH control (phys. salt)                                                                           1                                                           Compound no. 13., 20 mg/kg p.o. 5                                             Compound no. 5., 5 mg/kg p.o. 5                                               Compound no. 4., 5 mg/kg p.o. 5                                               Compound no. 10., 10 mg/kg p.o. 4                                             Compound no. 1., 20 mg/kg p.o. 3                                              Compound no. 11., 20 mg/kg p.o. 4                                             Compound no. 8., 5 mg/kg p.o. 3                                               Compound no. 9., 5 mg/kg p.o. 3                                               Compound no. 12., 5 mg/kg p.o. 4                                              Compound no. 14., 20 mg/kg p.o. 3                                             Captopril 100 mg/kg p.o. 3                                                  ______________________________________                                    

These experimental data also support the assumption that the compoundsof general formula (I) and (II) are able to regenerate the endotheliumnot only fulnctionally but morphologically as well. Upon chronictreatment these compounds resulted in more pronounced morphologicalregeneration than the reference substance Captopril.

EXAMINATION OF THE INFARCTED AREA ON SPONTANEOUSLY HYPERTENSIVE (SH)RATS AFTER ONE MONTH ORAL TREATMENT

Exerimental Groups

1. SH-age matched control

2. Verapamil (as a reference drug), 50 mg/kg p.o.

3. Compound No. 13., 20 mg/kg p.o.

4. Compound No. 13., 50 mg/kg p.o.

5. Compound No. 5., 5 mg/kg p.o.

6. Compound No.4., 5 mg/kg p.o.

Induction of Infarction

Myocardial ischaemia was induced by a temporary occlusion of the mainleft coronary artery, according to Griswold et al. (J. Pharmacol.Methods 1988. 20: 225-35). SH rats were anaesthetized with sodiumpentobarbital (50 mg/kg ip.). After tracheotomy, the animals wereventilated with room air by a respirator for small rodents (model:Harvard 552), with a stroke volume of 1,5-2 ml/100 g and a rate of 55strokes/min to maintain normal pO₂, PCO₂ and pH parameters.

The right carotid artery was catheterised and connected with a pressuretransducer (P236B Stetham) for the measurement of systemic arterialblood pressure (BP) by means of a preamplifier (Hg-O2D Experimetria®).Heart rate (HR) was measured by a cardiotachometer (HR-01,Experimetria®). The electrocardiogram (ECG standard lead III.) wasrecorded on a devices recorder (ER-14, Micromed®) by means ofsubcutaneous steel needle electrodes. The chest was opened by a leftthoracotomy and the heart was exteriorized by a gentle pressure on theright side of the rib cage.

A 4/0 silk ligature was quickly placed under the main left coronaryartery. The heart was replaced in the chest and the animal left torecover.

Rectal temperature was monitored and was maintained constant at 37° C.

The experimental protocol was initiated with a 15 min stabilisationperiod during which the observation of a sustained blood pressure lessthan 70 mmHg and/or the occurence of arrhythmias lead to exclusion.

Myocardial ischaemia was induced with coronary artery occlusion for 1hour and reperfusion allowed for 1 hour. Sham operated animals underwentto all the previously described surgical procedures except coronaryocclusion and reperfusion.

Quantification of Myocardial Infarction

At the end of experiment, the heart was quickly removed. The leftventricle was sliced into 2 mm thick sections parallel to theatrioventricular groove. The slices were incubated in a 0.1% solution ofNitroblue Tetrazolium grade III, pH 7,4 for 15 min. The non-infarctedarea was colored blue due to formation of a precipitate that resultsfrom reaction of NBT with dehydrogenase enzymes. Loss of these enzymesfrom infarcted myocardium prevents formation of the precipitate; thus,the infarcted area within the risk region remains pale yellow. The LVsections were photographed (Practica) and infarcted area was measured byplanimetry. The necrotic area was expressed as a percentage of thesurface of the left ventricle.

Statistical Analysis

All values will be expressed as mean ±SEM. Comparisons between groupswill be assessed by one-way ANOVA with post hoc analysis using theStudent ,,t" test. Statistical significance will be defined as p<0.05.

Results

There was no significant difference in the haemodynamic parameters, leftventricular and body weights among the groups.

                  TABLE 3                                                         ______________________________________                                        The infarct size and the survival rate of SH rats after coronary                artery occlusion and reperfusion                                                Groups        Infarct size (%)                                                                          Survival rate (%)                               ______________________________________                                        Control n = 9 42.7 ± 1.37                                                                            28.13                                                 Verapamil  24.3 ± 2.87** 53.3**                                            50 mg/kg n = 8                                                                Compound No. 13.   22.3 ± 3.6**,# 77.8**,#                                 20 mg/kg, n = 7                                                               Compound No. 13. 15.2 ± 3.7** 60.0**                                       50 mg/kg, n = 5                                                               Compound No. 5. 29.3 ± 2.9** 30.0                                          5 mg/kg, n = 3                                                                Compound No. 4. 25.6 ± 4.0** 71.4**,#                                      5 mg/kg, n = 5                                                              ______________________________________                                         **p < 0.01 vs control                                                         #p < 0.01 vs verapamil                                                   

Following coronary artery occlusion and reperfision, there was a markeddecrease in the survival rate of the control rats. Administration ofdifferent active compounds (except compound No. 5.) and the referencesubstance verapamil orally for one month significantly increased theresistance of rats to myocardial ischaemia/reperflsion injury.

Compared to verapamil, the improvement was significantly higher aftertreatment with compound No. 13. (20 mg/kg) and compound No. 4.

The active compounds and verapamil significantly reduced the infarctsize compared to the control animals. The infarct size limitation wasdose-dependent. The higher dose significantly reduced the extension ofthe myocardial necrosis compared to verapamil.

Our experiments indicate that selected active compounds significantlyreduced the extension of the myocardial necrosis and significantlyimproved the survival rate. Infarct size limitation occurred without anymarked changes in the haemodynamic parameters, and it was significantlyhigher after treatment with the compounds of the invention than afteradministration of the reference substance verapamil.

WOUNDING MIGRATION ASSAY

HUVEC cells were isolated and cultivated according to Jaffe E. A. et al.(J. Clin. Invest., 52, 2745-2756, 1973) The assay was carried out asdescribed by Yamamura S. et al. (J. Surg. Res., 63, 349-354, 1996).HUVEC cells were seeded on 96 well plate, previously coated withfibronectin (2 μg/well)(Sigma), and at appr. 90% confluency themonolayer was wounded along by coordinate line labeled backside of theplate. The layer injured with a Teflon cell scraper that was 1 mm inwidth. Well was rinsed and filled with completed RPMI 1640 medium(containing 5% of protein) for incubation (at 37° C. in 5% CO₂containing air). Cells were allowed to migrate for 24 and 48 hours ontothe wounded field and camera or photographs were taken through aninverted microscope (at ×60 magnification) to recording. The numbers ofcells that were moved beyond the reference line counted and evaluated byimage analyzer.

Treatment with the Test Compound

A serial ten step fold dilution were prepared in medium added 5 μl/wellcontaining 95 μl of tissue culture over the wounded cell monolayer. Thecontrol culture contained no dilution of compound No. 13.

Results

After 24 hour incubation the cells spontaneously appeared in the woundedarea and even an increased number was counted in the presence of testcompound at a submicromolar concentration (at 10⁻⁷ and 10⁻⁸ M). testcompound resulted an emphatic, considerable promotion on cell migrationeven 48 hrs period. The wounded area was covered about 82% compared to47% with the spontaneous migrated human endothelial cells.

                  TABLE 4                                                         ______________________________________                                        Results of the wounding migration test with compound No. 13.                               The covered area                                                 Doses        cell/mm.sup.2      %/mm.sup.2                                    10.sup.-8 (M)                                                                              24 h   48 h        24 h 48 h                                     ______________________________________                                        7            689    1009        56   82                                         8 750 948 61 80                                                               Non-treated* 480 578 39 47                                                  Adhered cells**                                                                            180                 6                                            ______________________________________                                         *Non treated control, spontaneous migration,                                  **Cells on the injured surface immediately after wounding start, control      situation.                                                               

The repair process of damaged vascular monolayer is started withmigration of endothelial cells by that way may flrther initializedreconstruction of injured area. All our data suggest that test compoundmay promote repair on wounded human endothelial cells with directenhancement of migration.

The invention is illustrated in the following examples without anylimitation on the scope claimed:

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1N-[2-benzoyloxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidamide(Z)-2-butenedioate (1:1) (Compound No. 1.)

Procedure

20.9 g (75.0 mmol) ofN-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine-carboximidamide [Hung.Pat. 177.578 (1976)] was dissolved in 300 ml of benzene. To thissolution 150 ml of 1 N sodium hydroxide solution was added, followed bydropwise addition of 19.5 ml (168 mmol) of benzoylchloride. Afterstirring the mixture intensively for 2 hours, 7.1 g (67 mmol) of sodiumcarbonate and a further portion of benzoylchloride (9.75 ml; 84 mmol)was added, and the stirring was continued overnight. The phases werethen separated, the organic layer was extracted with 1N sodium hydroxidesolution and water, dried and evaporated to dryness. The residue (41 goil) was dissolved in 150 ml of acetone, and 8.7 g (75 mmol) maleic acidwas added. The obtained precipitate was filtered off, washed withacetone, and dried.

Yield: 29.0 g (78%), Mp.: 194-195° C.

Example 2N-[2-palmitoyloxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidamideMonohydrochloride (Compound No. 2.)

Procedure

14.7 g (52.8 mmol) ofN-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine-carboximidamide [Hung.Pat. 177.578 (1976)] was dissolved in 160 ml of chloroform. 7.7 ml (55mmol) of triethylamnine was added, followed by dropwise addition of asolution of palmitoylchloride (14.7 g; 56.5 mmol) in 85 ml ofchloroform. The mixture was stirred overnight at room temperature. Nextday further amount of 3.8 ml of triethylamine and 7.4 g ofpalmitoylchloride was added, and the stig was continued for one moreday. The solution was extracted then with water, 5% acetic acid andwater, successively, dried over anh. sodium sulphate, and evaporated todryness.

The residue (28.2 g oil) was dissolved in ethyl-acetate, and the productwas precipitated by addition of 30 ml of 1N HCl/ethyl acetate. Thethick, white precipitate was filtered off, washed with ethyl acetate anddried.

Yield: 10.9 g (37%), Mp.: 110-113° C.

Example 3N-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3-trifluoromethylbenzenecarboximidoylChloride Monohydrochloride (Compound No. 3.)

Procedure

Step a)

50 g (0.245 mol) of m-trifluoromethyl-benzamidoxime and 33.7 g (0.6 mol)of potassium hydroxide was dissolved in a mixture of dimethyl sulphoxideand 170 ml of water, and the mixture was cooled to 0° C. 48 ml (0.6 mol)of epichlorohydrin was added, and the reaction mixture was stirred at 0°C. for 5 hours, then kept in a refrigerator overnight. Next day 250 mlof water was added, and the mixture was extracted with ethyl acetate(4×250 ml). The combined organic phases were washed with water, dried,treated with charcoal and evaporated to dryness, to yieldm-trifluoromethyl--N-(2,3--poxypropoxy)-benzanidine, as a colourlessoil.

Yield: 61 g (96%)

Step b)

To the obtained oil 400 ml of 18% of hydrochloric acid solution and 60ml of ether were added, and the mixture was cooled to -5° C., whilestirring. 17.4 g (0.25 mol) of sodium nitrite, dissolved in 60 ml ofwater was added slowly in 40 min., and the reaction mixture was stirredfor another 20 minutes. The mixture was extracted then with ether (2×160ml), and the combined organic phases were washed with water twice. Tothe ethereal solution 340 ml of 20% of sodium hydroxide solution wasadded, and the two-phase system was refluxed for 1 hour, while stirring.The phases were then separated, the organic layer was washed with brineuntil neutral, dried and evaporated to dryness to givem-trifluoromethyl-N-(2,3-epoxypropoxy)-benzimidoyl chloride, as acolourless oil.

Yield: 30.5 g (45%)

Step c)

A mixture of 1.19 g (4.2 mmol)N-[(2,3-epoxy)propoxy]-3-trifluoromethylbenzenecarboximidoyl chlorideand 0.89 ml (8.5 mrnol) of tert-butylamine in 12 ml of isopropyl alcoholwas refluxed for 2 hours. Solvent was removed under reduced pressure.The residue was dissolved in ethyl acetate, and 0.98 ml of methanolichydrogen chloride solution (4.3N) was added and the mixture wasconcentrated to small volume under vacuum, then diluted with ether. Theprecipitate that formed was recovered, washed with cold ether and dried.

Yield: 0.4 8 g (32%), Mp.: 150-153° C.

IR (KBr): 3423, 3233, 2978, 2880, 2784, 1620,1570, 1479, 1441,1400,1383, 1340, 1238, 1167, 1128, 1101, 1072, 1038, 982, 930, 897, 804,787, 714, 694 cm⁻¹

Example 4N-[2-hydroxy-3-(1-piperidinyl)propoxy]-2-thiophenecarboximidoyl ChlorideMonohydrochloride (Compound No.4.)

Procedure

5.0 g (15.6 mmol) ofN-[2-hydroxy-3-(1-piperidinyl)propoxy]-2-thiophenecarboximidamidemonohydrochloride was dissolved in 19 ml of water, then 6.1 ml ofconcentrated hydrochloric acid was added. The solution was cooled to -5°C., then a cold solution of 4.4 g (63.8 mmol) of sodium nitrite in 2.4ml of water was added dropwise. Throughout the reaction the internaltemperature was maintained at 0° C. When addition was completed themixture was stirred for a further one hour. Cold benzene (60 ml) wasadded and the mixture was made alkaline with slow addition of a coldsolution of 3.2 g (80 mmol) of sodium hydroxide in 45 ml of water. Theorganic phase was separated and washed successively with 20 ml portionsof water until the pH<9 (3-5 times). The organic solution was dried overanhydrous sodium sulphate, treated with charcoal, filtered andevaporated in vacuum (t<45° C.) to give 2.6 g of oil. This residue wasdissolved in 5 ml of isopropyl alcohol and acidified (pH 2) withisopropyl alcohol containing dry hydrochloric acid. The product wascrystallised from n-hexane to give off-white material.

Yield: 2.0 g (38%), Mp.: 115-123° C.

Following the process described in the previous example the followingcompounds were prepared:

Example 5 N-[2-hydroxy-3-(1-piperidinyl)propoxy]-benzenecarboximidoylChloride Monohydrochloride (Compound No. 5.)

Starting material:N-[2-hydroxy-3-(1-piperidinyl)propoxy]-benzenecarboximidamide

Yield: 23%, Mp.: 140-145° C.

Example 6 N-[2-hydroxy-3-(1-piperidinyl)propoxy]-4-pyridinecarboximidoylChloride (Z)-2-butenedioate (1:1) (Compound No. 6.)

Starting material:N-[2-hydroxy-3-(1-piperidinyl)propoxy]-4-pyridinecarboximidamide In thiscase the final product was isolated at the end of the work-up procedureby dissolving the crude base in acetone, and adding an equivalent amountof maleic acid.

Yield: 25%, Mp.: 150-154° C.

Example 7N-[2-hydroxy-3-(1-piperidinyl)propoxy]-2-nitrobenzenecarboximidoylChloride Monohydrochloride (Compound No. 7.)

Starting Material

N-[2-hydroxy-3-(1-piperidinyl)propoxy]-2-nitrobenzenecarboximidamide

Yield: 36%, Mp.: 158-162° C.

Example 8 Hiba! A konyvjelzo nem letezikN-(3-(1-piperidinyl)propoxy)-3-pyridinecarboximidoyl ChlorideDihydrochloride (Compound No. 8.)

Starting material:N-[3-(1-piperidinyl)propoxy]-3-pyridinecarboximidamide

Yield: 33%, Mp.: 178-182° C.

Example 9 N-[3-(1-piperidinyl)propoxy]-3-nitrobenzenecarboximidoylChloride Monohydrochloride (Compound No. 9.)

Starting material:N-[3-(1-piperidinyl)propoxy]-3-nitrobenzenecarboximidamide

Yield: 49%, Mp.: 173-175° C.

Example 10N-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3-trifluoromethyl-benzamide(Compound No. 10.)

Procedure

1.3 ml (15.2 mmol) of epichlorohydrin was added to a solution of 1.6 ml(15.2 mmol) of tert-butylamine in 8 ml of ethanol during 10 minutes withstirring, keeping the temperature below 20° C., and allow to stand for 3days. Separately, 0.8 g (14.3 mmol) of potassium hydroxide was dissolvedin a mixture of 20 ml of ethanol and 3 ml of water and into thissolution 3.42 g (15.2 mmol) of N-hydroxy-3-(trifluoromethyl)-benzamidepotassium salt and the formerly prepared solution of epichlorohydrin andtert-butylamine were added. The reaction mixture was stirred and boiledfor 10 hours, then the solvent was evaporated. The residue wastriturated with 20 ml of dichloromethane and 10 ml of water, the organicphase was separated, washed with 5 ml of water and 5 ml of saturatedsodium chloride solution, dried over sodium sulphate, filtered andevaporated. The oily residue was crystallised in a mixture ofacetone-hexane to yield white powder as title compound.

Yield: 0.85 g (17.3%), Mp.: 156-158° C.

IR (KBr): 2976, 2858, 1612, 1556, 1379, 1352, 1313, 1273, 1165, 1130,1072, 694 cm⁻¹

Example 11 N-hexyl-N'-[2-hydroxy-3-(1-piperidinyl)propox]-urea (CompoundNo. 11.)

Procedure

To the solution of 8.0 g (45.9 nmol) of1-aminooxy-2-hydroxy-3-(1-piperidinyl)-propane dissolved in 60 ml ofchloroform 4.9 ml (45.9 mmol) of hexylisocyanate was added and thereaction mixture was stirred for 20 hours at room temperature. Afteraddition of a further 1.6 ml (15 mmol) of hexylisocyanate, the stirringwas continued for two more hours, when the solvent was evaporated invacuum. White crystalline product was obtained by triturating withpetroleum ether.

Yield: 9.9 g (72%), Mp.: 50-52° C.

IR (KBr): 3310, 2932, 2858, 2804, 1666, 1551, 1454, 1377, 1306, 1092,1040, 995, 791, 725, 604 cm⁻¹

Following the process described in the previous example the followingcompounds were prepared:

Example 12 N-hexyl-N'-[3-(1-piperidinyl)propoxy]-urea (Compound No. 12.)

Starting material: 1-aminooxy-3-(1-piperidinyl)-propane

Yield: 85% (oil)

IR (KBr): 3354, 2932, 2856, 2810, 2777, 1666, 1543, 1486, 1377, 1308,1155, 1134, 1076 cm⁻¹

Example 135,6-Dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxodiazine

Procedure

Step a)

17.5 g (0.05 mole) ofN-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarbox-imidamidedihydrochloride was dissolved in 50 ml of thionyl chloride, boiled forone hour, then the mixture was evaporated to dryness. The residue wasdissolved in 300 ml of methanol, treated with charcoal and afterfiltration the solvent was evaporated in reduced pressure. The residuewas dissolved in the minimum amount of ethanol and refrigerated to yieldcrystallineN-[2-chloro-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidamidedihydrochloride as intermediate compound.

Yield: 13.2 g (71%), Mp.: 127-145° C.

Step b)

13.2 g (35.7 mrnmole) ofN-[2-chloro-3-(1-piperidinyl)propoxy]-3-pyridinecarbox-imidamidedihydrochloride was added to a solution of 16.5 g (143.5 mmole) ofpotassium tert-butoxide dissolved in 150 ml of tert-butanol. The mixturewas boiled for 6 hours, then evaporated in vacuum. 100 ml of 5% sodiumhydroxide solution was added and the mixture was extracted three timeswith 300 ml portions of ethyl acetate. The organic layer was dried oversodium sulphate, filtered and evaporated to dryness. The residue wastriturated with diethyl ether to yield the title compound as whitecrystals.

Yield: 3.5 g (38%), Mp.: 157.5-158° C.

Example 14 Tablets

For the production of 200 mg tablets containing 50 mg of effectivesubstance use:

50 mg of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-benzenecarboximidoylchloride monohydrochloride

129 mg of microcrystalline cellulose (e.g. "Avicel ph 102")

20 mg of polyvinyl-pirrolidone (e.g. "Polyplasdone XL")

1 mg of magnesium stearate

Example 15 Capsules

For a 300 mg capsule use:

50 mg ofN-[2-hydroxy-3-(1-piperidinyl)propoxy]-2-nitro-benzenecarboximidoylchloride monohydrochloride

10 mg of yellow bee wax

10 mg of soybean oil

130 mg of vegetable oil

100 mg of capsule cell

Example 16 Solution

For 100 ml solution use:

500 mg ofN-[2-hydroxy-3-(1-piperidinyl)propoxy]-2-thiophenecarboximidoyl chloridemonohydrochloride

10 g of sorbit

0.05 g of saccharine sodium

ad 100 ml of twice distilled water.

Example 17 Injection Vial

For each 2 ml injection vial containing 2 mg of effective substance use:

2 mg of5,6-Dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine

ad 2.0 ml of physiological saline solution, pyrogen-free, sterile.

Example 18 Infusion Solution

For 500 ml of infusion solution use:

20 mg of N-hexyl-N'-[3-(1-piperidinyl)propoxy]-urea

ad 500 ml of physiological saline solution, pyrogen-free, sterile.

What is claimed is:
 1. A method of treating or preventing. illnessesresulting from damaged endothelial cells said methodcomprising:administering to a patient hydroxylamine derivatives of thegeneral formulae ##STR3## wherein R¹ and R² independently comprise ahydrogen atom or a straight or branched alkyl group of 1 to 6 carbonatoms, or R¹ and R² together with the nitrogen atom in-between form asaturated 5-7 membered heterocyclic group, optionally containingadditional nitrogen and/or oxygen heteroatoms, A comprises a straight orbranched alkyl group of 4 to 12 carbon atoms, a phenyl group,substituted or unsubstituted, optionally containing an alkyl-,haloalkyl- or nitro group as substituent, or a 5-6 memberedheteroaromatic ring containing nitrogen, oxygen or sulphur, in generalformula (I) Z comprises a covalent bond, and in general formula (II) Zcomprises a covalent bond or a ═NH group, in general formula (I) Xcomprises a halogen atom or to a --NR³ R⁴ group, wherein R³ and R⁴independently comprise a hydrogen atom or a straight or branched alkylgroup of 1 to 6 carbon atoms, while in general formula (II) X comprisesan oxygen atom, in general formula (II) R' comprises a hydrogen atom ora straight or branched alkyl group of 1 to 6 carbon atoms, and ingeneral formulae (I) and (II) Y comprises a hydrogen atom, a hydroxylgroup or an acyloxy group, which optionally contains the acyl part of along chain fatty acid of 8 to 22 carbon atoms, or of a cyclic aromaticcarboxylic acid as its acyl component, and in the compounds of generalformula (I) when X comprises a --NR³ R⁴ group and Y comprises a hydroxylgroup, the X group is condensed with the Y substituent to form theintramolecular ring represented by general formula (III), ##STR4## inwhich formula A, Z, R¹ and R² comprise the elements defined above or thesalts and optically active forms thereof.
 2. The method according toclaim 1, wherein said method comprises usingN-[2-benzoyloxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidamide(Z)-2-butenedioate (1:1) as an active ingredient.
 3. The methodaccording to claim 1, wherein said method comprises usingN-[2-palmitoyloxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidamidemonohydrochloride as an active ingredient.
 4. The method according toclaim 1, wherein said method comprises usingN-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3-trifluoromethylbenzenecarboximidoylchloride monohydrochloride as an active ingredient.
 5. The methodaccording to claim 1, wherein said method comprises usingN-[2-hydroxy-3-(1-piperidinyl)propoxy]-2-thiophenecarboximidoyl chloridemonohydrochloride as an active ingredient.
 6. The method according toclaim 1, wherein said method comprises usingN-[2-hydroxy-3-(1-piperidinyl)propoxy]-benzenecarboximidoyl chloridemonohydrochloricle as an active ingredient.
 7. The method according toclaim 1, wherein said method comprises usingN-[2-hydroxy-3-(1-piperidinyl)propoxy]-4-pyridinecarboximidoyl chloride(Z)-2-butenedioate as an active ingredient.
 8. The method according toclaim 1, wherein said method comprises usingN-[2-hydroxy-3-(1-piperidinyl)propoxy]-2-nitrobenzenecarboximidoylchloride monohydrochloride as an active ingredient.
 9. The methodaccording to claim 1, wherein said method comprises usingN-[3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloridedihydrochloride as an active ingredient.
 10. The method according toclaim 1, wherein said method comprises usingN-[3-(1-piperidinyl)propoxy]-3-nitrobenzenecarboximidoyl chloridemonohydrochloride as an active ingredient.
 11. The method according toclaim 1, wherein said method comprises usingN-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3-trifluoromethyl-benzamideas an active ingredient.
 12. The method according to claim 1, whereinsaid method comprises usingN-hexyl-N'-[2-hydroxy-3-(1-piperidinyl)propoxy]-urea as an activeingredient.
 13. The method according to claim 1, wherein said methodcomprises using N-hexyl-N'-[3-(1-piperidinyl)propoxy]-urea as an activeingredient.
 14. The method according to claim 1, wherein said methodcomprises using 5, 6-dihydro-5-(1-piperidinyl)methyl-3-(-pyridyl)-4H-1,2,4-oxadiazine as an active ingredient.
 15. A pharmaceutical productfor the treatment and prevention of illnesses resulting from damagedvascular endothelial cells, said product comprising, as an activeingredient, 0.5-95.5 m/m % of a hydroxylamine derivative represented bygeneral formula (I) ##STR5## or the salts of optically active formsthereof, wherein R¹ and R² independently comprise a hydrogen atom or astraight or branched alkyl group of 1 to 6 carbon atoms, or R¹ and R²together with the nitrogen atom in-between form a saturated 5-7 memberedheterocyclic group, optionally containing additional nitrogen and/oroxygen heteroatoms,A comprises a straight or branched alkyl group of 4to 12 carbon atoms, a phenyI group, substituted or unsubstituted,containing an alkyl-, haloalkyl- or nitro group as substituent, or a 5-6membered heteroaromatic ring containing nitrogen, oxygen or sulphur, ingeneral formula (I) Z comprises a covalent bond, and in general formula(II) Z comprises a covalent bond or a ═NH group, in general formula (I)X comprises a halogen atom or a --NR³ R⁴ group, wherein R³ and R⁴independently comprise a hydrogen atom or a straight or branched alkylgroup of 1 to 6 carbon atoms, while in general formula (II) X comprisesan oxygen atom, in general formula (II) R' comprises a hydrogen atom ora straight or branched alkyl group of 1 to 6 carbon atoms, and ingeneral formulae (I) and (II) Y comprises a hydrogen atom, a hydroxylgroup or an acyloxy group, which contains the acyl part of a long chainfatty acid of 8 to 22 carbon atoms, or of a cyclic aromatic carboxylicacid as its acyl component, and in the compounds of general formula (I)when X comprises a --NR³ R⁴ group and Y comprises a hydroxyl group, theX group is condensed with the Y substituent to form the intramolecularring represented by general formula (III), ##STR6## in which formula A,Z, R¹ and R² comprise the elements defined above or the salts andoptically active forms thereof.